ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells.
ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells.
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DOI：
10.1186/s12885-018-4758-y
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发表时间：
2018-08-24
期刊：
影响因子：
3.8
通讯作者：
Matuskova M
中科院分区：
文献类型：
--
作者：
Durinikova E;Kozovska Z;Poturnajova M;Plava J;Cierna Z;Babelova A;Bohovic R;Schmidtova S;Tomas M;Kucerova L;Matuskova M
随着患者的耐药性随着时间的推移而发展，化疗治疗结直肠癌的效率会降低。用于结直肠癌一线化疗的药物 5-氟尿嘧啶也是如此。通过在增加浓度的5-氟尿嘧啶中长期培养来制备HT-29细胞的化学抗性衍生物。通过活力测定、流式细胞术、基因表达阵列和动力学成像对细胞进行表征。免疫磁性分离用于分离癌症干细胞相关表面标记物呈阳性的亚群。 siRNA 减弱了醛脱氢酶的表达。在 SCID/bg 小鼠上进行体内研究。与亲本对应物 HT-29/EGFP 相比，制备的标记为 HT-29/EGFP/FUR 的化学抗性细胞系具有不同的形态、增殖率降低和 5-氟尿嘧啶的 IC50 值增加 135 倍。当化疗耐药细胞皮下注射到 SCID/bg 小鼠体内时，其形成肿瘤异种移植物的能力受到严重损害，但它们会在小鼠肺部自发形成远处转移。即使没有 5-氟尿嘧啶选择压力，衍生细胞在体外和体内仍保持其抵抗力。更重要的是，它们对顺铂、奥沙利铂和环磷酰胺具有耐药性，表现出高度交叉耐药性，并且癌症干细胞标志物（例如 CD133、CD166、CD24、CD26、CXCR4、CD271 和 CD274）的表达发生变化。我们还检测到与特定 ALDH 异构体 1A3 过度表达相关的乙醛脱氢酶 (ALDH) 活性增加。 siRNA 的抑制作用使细胞对各种药物部分敏感，从而首次将 ALDH1A3 与结直肠癌的化疗耐药性联系起来。我们的研究表明，获得性化疗耐药性伴随着转移和迁移表型，并且可能伴随着乙醛脱氢酶活性的增加。我们在这里描述了研究化疗耐药性和转移性播散之间分子联系的有价值的模型。
Efficiency of colorectal carcinoma treatment by chemotherapy is diminished as the resistance develops over time in patients. The same holds true for 5-fluorouracil, the drug used in first line chemotherapy of colorectal carcinoma. Chemoresistant derivative of HT-29 cells was prepared by long-term culturing in increasing concentration of 5-fluorouracil. Cells were characterized by viability assays, flow cytometry, gene expression arrays and kinetic imaging. Immunomagnetic separation was used for isolation of subpopulations positive for cancer stem cells-related surface markers. Aldehyde dehydrogenase expression was attenuated by siRNA. In vivo studies were performed on SCID/bg mice. The prepared chemoresistant cell line labeled as HT-29/EGFP/FUR is assigned with different morphology, decreased proliferation rate and 135-fold increased IC50 value for 5-fluorouracil in comparison to parental counterparts HT-29/EGFP. The capability of chemoresistant cells to form tumor xenografts, when injected subcutaneously into SCID/bg mice, was strongly compromised, however, they formed distant metastases in mouse lungs spontaneously. Derived cells preserved their resistance in vitro and in vivo even without the 5-fluorouracil selection pressure. More importantly, they were resistant to cisplatin, oxaliplatin and cyclophosphamide exhibiting high cross-resistance along with alterations in expression of cancer-stem cell markers such as CD133, CD166, CD24, CD26, CXCR4, CD271 and CD274. We also detected increased aldehyde dehydrogenase (ALDH) activity associated with overexpression of specific ALDH isoform 1A3. Its inhibition by siRNA approach partially sensitized cells to various agents, thus linking for the first time the ALDH1A3 and chemoresistance in colorectal cancer. Our study demonstrated that acquired chemoresistance goes along with metastatic and migratory phenotype and can be accompanied with increased activity of aldehyde dehydrogenase. We describe here the valuable model to study molecular link between resistance to chemotherapy and metastatic dissemination.
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影响因子：
3.8
作者：
Flahaut M;Jauquier N;Chevalier N;Nardou K;Balmas Bourloud K;Joseph JM;Barras D;Widmann C;Gross N;Renella R;Mühlethaler-Mottet A
通讯作者：
Mühlethaler-Mottet A
影响因子：
6.4
作者：
Ertem, Furkan U.;Zhang, Wenqian;Dashwood, Roderick H.
通讯作者：
Dashwood, Roderick H.
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
5.3
作者：
Gunaratne, Adrian;Thai, Boun L.;Di Guglielmo, Gianni M.
通讯作者：
Di Guglielmo, Gianni M.
了解和靶向癌症干细胞：治疗意义和挑战
影响因子：
8.2
作者：
Chen, Ke;Huang, Ying-hui;Chen, Ji-long
通讯作者：
Chen, Ji-long